1-nitrosopyrrolidines

ABSTRACT

1-Nitrosopyrrolidines having anticonvulsant activity are disclosed. The compounds are prepared from 3-(mono- and disubstituted)pyrrolidines by nitrosation. Substituents in the 3position are selected from a combination of hydroxyl, Alpha phenyl- Alpha -hydroxybenzyl, Alpha -alkyl- Alpha hydroxybenzyl, phenyl, trifluoromethylphenyl and phenoxy radicals.

Elniied States Parent Helsley [54] l-NITROSOPYRROLIDINES [72] Inventor:Grover Cleveland Richmond, Va.

Helsley,

[73] Assignee: A. H. Robins Company, Incorporated, Richmond, Va.

[22] Filed: Aug. 31, 1970 [21] Appl. No.: 68,590

[52] US. CL... ..260/326.5 L, 260/3265 R, 260/326.85,

424/274 [51] Int. Cl. ..C07d 27/02 [58] Field of Search ..260/326.5 R,326.8

[451 Sept. 26, 1972 [56] References Cited UNITED STATES PATENTS3,090,786 5/1963 Levering et al ..260/293 Primary Examiner-Alex MazelAssistant Examiner-Joseph A. Narcavage Attorney-G. William King andNorman D. Dawson ABSTRACT 7 Claims, No Drawings avan-qr;

. l l-NITROSOPYRROLIDINES Formula I wherein; x

R is selected from hydrogen and hydroxy, and R is selected froma-phenyl-a-hydroxybenzyl, alower-alkyl-a-hydroxybenayl,a-lower-alkyl-ahydroxy-p-trifluoromethylbenzyl, phenyl,trifluoromethylphenyl and 3,5-di-lower-alkyl phenoxy.

The compounds of the present invention have demonstrated utility asanticonvulsants in animals as determined by recognized pharmacologicalprocedures. When convulsions were induced in mice using the supramaximalelectroshock technique of Toman, J. E. P. et al., J. Neurophysiol. 9,47(1946), anticonvulsant protection was afforded when the compounds weregiven intraperitoneally at dose levels of to 200 mg./kg. and preferablyat 20 to 80 mgJkg. The compounds of Examples 1, 2, and 3 affordedsignificant protection against pentylenetetrazole-induced convulsions inmice when administered intraperitoneally at a dose level of -30 to 200mg./kg. and preferably at 40 to 100 mg./kg. The procedure of Swinyard etal, J. Pharm. Exptl. Therap. 106, 3 l9( l959) was used.

Pharmacological data for the preferred compounds of the invention islisted in Table I below. The ED s were determined using the method ofLitchfield and Wilcoxin, J. Pharrn. Exptl. Therap., 96; 99( 1949).

TABLE I Electroshock ED mgJkg. 55

It is, therefore, an object of the present invention to provide novell-nitrosopyrrolidines useful as anticonvulsants. Other objects andadvantages of this invention will be apparent to one skilled in the art,and still others will become apparent hereinafter.

In the definition of symbols in Formula I and where they appearelsewhere throughout this specification and in the claims, the termshave the following significance.

Lower alkyl includes straight and branched chain radicals of up to eightcarbon atoms and is exemplified by such groups as methyl, ethyl, propyl,butyl, isopropyl, isobutyl, amyl, hexyl, heptyl, octyl, isooctyl and thelike.

The novel compounds of the present invention having a nitro substituentin the l-position of the pyrrolidine nucleus are prepared by thereaction of a 3- (monoand disubstitutecl) pyrrolidine with sodiumnitrite in an aqueous acidic medium. The selected pyrrolidine isdissolved in dilute mineral acid, preferably dilute hydrochloric acid.An aqueous solution of sodium nitrite is slowly added to the stirredaqueous acidic solution which is maintained at a temperature of fromabout 50 C. to about 80 C., and preferably at about C. The stirredreaction mixture is maintained at about 70 C. for an additional periodof time of from about 1 hour to 3 hours. The reaction mixture is cooledand the crude product either precipitates from the cooled reactionmixture, or it is extracted with an organic solvent such as chloroform.The crude product is purified by crystallization from a suitable solventor by vacuum distillation.

The following preparations and examples are given by way of illustrationonly and are not to be construed as limiting.

PREPARATION OF INTERMEDIATES The 3-(monoand disubstituted) pyrrolidineintermediates used in the preparation of the novel l-nitroso- 3-(monoanddisubstituted) pyrrolidine of the present invention are known to the artand are either disclosed in the US. Pat. Nos. 2,787,264 and 3,479,370,or they can be prepared by the methods disclosed therein. Otherintermediates can be prepared as shown by the following preparations.

PREPARATION l 3-(m-Trifluoromethylphenyl) Hydrochloride A solution of11.5 g. (0.05 mole) of 3-(mtrifluoromethylpheny)-3-pyrrolidinol in 200ml. of 6N hydrochloric acid containing 4 g. of 10 percentpalladium-on-charcoal catalyst was shaken in three atmospheres ofhydrogen until one equivalent of hydrogen was absorbed. After cooling,the suspension was filtered and made basic with 50 percent sodiumhydroxide. The oil which separated was extracted with ether and thecombined extracts were washed with water. After drying over magnesiumsulfate the solvent was evaporated. The non-viscous residual oil weighed7.1 g. (65 percent yield). An ether solution of the free base wastreated with an ether-hydrogen chloride solution and the hydrochloridesalt which formed on standing was recrystallized from anisopropanol-isopropyl ether mixture; the hydrochloride salt melted at l1 l-l 1 pyrrolidine Analysis: Calculated for c l-l ClNF z C,52.49;H,5.2l; N,5.57 Found: C,52.34; H,5.2 N,5.54

PREPARATION 2 l-Benzyl-3-( 3 ,S-dimethylphenoxy )pyrrolidineHydrochloride A stirred mixture of 244 g. (2.0 moles) of 3,5-dimethylphenol, 391 g. (2.0 moles) of l-benzyl3- chloropyrrolidine, 108g. (2.0 moles) of sodium methoxide and one liter of dimethylformamidewas heated at 1l0l 14 C. for 16 hours, cooled and treated with 1 literof water. The oil which separated was extracted with benzene and wassuccessively washed with 5 percent sodium hydroxide and water. Thebenzene layer was dried over magnesium sulfate and the benzene wasevaporated from the dried solution. The residual oil was distilled atl45-l48 C./.05 mm.; the distillate weighed 154 g. (24 percent yield). Aportion of the free base in dry ether was treated with ethereal hydrogenchloride and the white crystalline hydrochloride which formed wasrecrystallized from an isopropanol-isopropyl ether mixture. Thehydrochloride melted at 15 8-160.5 C.

Analysis: Calculated for CWHHNOCI:

c, 71.79; H, 7.61; N, 4.41 Found: C, 71.64; H 7.58; N, 4.45

PREPARATION 3 I 3-(3,5 -Dimethylphenoxy)pyrrolidine Hydrochloride.

Calculated for C H NOCl:

Analysis:

H, 7.97; Found H, 7.94;

EXAMPLE 1 l-Nitroso-a,a-diphenyl- 3-pyrrolidinemethanol To a solution of15 g. (0.059 mole) of a,a-diphenyl-3 -pyrrolidine methanol in 55 ml. of1.0 N hydrochloric acid maintained at ca. 70 C. was added slowly asolution of 4.2 g. (0.061 mole) of sodium nitrite in 20 ml. of water.The mixture was stirred for 2 hours at the same temperature, thencooled, and extracted with chloroform. The combined chloroform extractswere dried and the solvent was evaporated at reduced pressure yielding9.1 g. (55 percent) of crude product which crystallized on standing. Asample was recrystallized from isopropanol-isopropyl ether and melted atAnalysis: Calculated for C H ,N,O,:

C,72.32; 11.6.43; N,9.92 Found C,72.64; H,6.38; N,9.84

EXAMPLE 2 1-Nitroso-a-phenyl-a-propyl-3-pyrrolidinemethanol To asolution of 6.0 g. (0.028 mole) of a-phenyl-apropyl-3-pyrrolidinemethanol in 29 ml. of 1.0 N hydrochloric acid maintained atca. C. was added slowly a solution of 2.0 g. (0.029 mole) of sodiumnitrite in 15 ml. of water. The mixture was stirred for 2 hours at thesame temperature, cooled and the crystalline product which formed wasseparated by filtration. The white product weighed 4.7 g. (69 percent)and melted at l29-l 3 1 C. The product melted at l31.51 32.5C. after itwas recrystallized from isopropyl thp Analysis: Calculated for CH,N,O,:

EXAMPLE 3 Analysis: Calculated for C H 5N 0 H,5.25; N,9.72 Found:H,5.23; N,9.56

EXAMPLE 4 l-Nitroso-3-( m-trifluoromethylphenyl )-3-pyrrolidinol To asolution of 5.0 g. (0.022 mole) of 3-m-(trifluoromethylphenyl)-3-pyrrolidinol in 50 ml. of water and 1.9 ml. ofconcentrated hydrochloric acid at ca. 70 C. was added slowly a solutionof 1.6 g. (0.023 mole) of sodium nitrite in 25 ml. of water. Thereaction mixture was stirred for an additional 2 hours at the sametemperature, cooled, and extracted with benzene. The combined extractswere washed, dried over magnesium sulfate and the solvent evaporated atreduced pressure. The residual oil which crystallized on triturationwith isopropyl ether was recrystallized from the same solvent yielding2.8 g. (49 percent) of white product melting at 104-l 05 C.

Analysis: Calculated for C H F N O C,50.77; Found C,50.74;

EXAMPLE 5 l-Nitroso-3-(m-trifluoromethylphenyl)pyrrolidine To a stirredsolution of 5.8 g. (0.027 mole) of 3-(mtrifluoromethylphenyl)pyrrolidinein 54 ml. of 0.5 N hydrochloric acid at ca. 70 C. was added slowly asolution of 1.9 g. (0.027 mole) of sodium nitrite in 30 ml. of water.The reaction mixture was stirred for an additional 2 hours at the sametemperature, then cooled and extracted with benzene. The combinedextracts were washed successively with dilute hydrochloric acid andwater and then dried over magnesium sulfate. After the solvent wasevaporated from the dried solution the residual oil was distilled at122-124 C./0.05 mm. The light yellow, non-viscous oil weighed 2.9 g.

(44 percent yield).

Analysis: Calculated for c l-l F N O:

, C,54.09; H,4.54; N,l 1.47 Found: c.5382; H,4.56; N,'l 1.29

EXAMPLE 6 Analysis: Calculated for c n u o z C,65.43; 11,7.32; N,l2.72Found: C,65.29; H,7.37; N,l2.62

FORMULATION AND ADMINISTRATION Useful compositions containing at leastone of the compounds according to the invention in association with apharmaceutical carrier or excipient may be prepared in accordance withconventional technology and procedures. Thus, the compounds may bepresented in a form suitable for oral or parenteral administration. Forexample, compositions for oral administration can be solid or liquid andcan take the form of capsules, tablets, coated tablets and suspensions,such compositions comprising carriers and excipients conveniently usedin the pharmaceutical an. Suitable tableting excipients include lactose,potato and maizestarches, talc, gelatin, and stearic and silicic acids,magnesium stearate and polyvinyl-pyrrolidone.

For parenteral administration the carrier or excipient may be a sterile,parenterally acceptable liquid; e.g., water or a parenterally acceptableoil, arachis oil contained in ampules.

Advantageously, the compositions may be formulated as dosage units, eachunit being adapted to supply a fixeddose of active ingredients. Tablets,capsules, coated tablets and ampoules are examples of preferred dosageunit forms according to the invention. Each dosage unit adapted for oraladministration can conveniently contain one to 50 mg. and preferably 5to mg. of the active ingredient. It is only necessary that the activeingredient constitute an effective amount; i.e., such that a suitableeffective dosage will be obtained consistent with the dosage formemployed. Obviously, several unit dosage forms may be administered atabout the same time.

The following are examples of compositions formed in accordance withthis invention.

1. Capsules Capsules of l, 20 and 50 mg. of active ingredient percapsule are prepared. With the higher amounts of active ingredient,reduction may be made in the amount of lactose.

Typical blend for encapsulation Per capsule. mg.

Active ingredient 10.0 Lactose 291.7 Starch 129.0 Magnesium stearate 4.3

Total 435.0

2. Tablets A typical formulation for a tablet containing 50 mg. ofactive ingredient per tablet follows. The formulation may be used forother strengths of active ingredient by adjustment of weight ofdicalcium phosphate.

50 mg. Tablet Ingredients Per Tablet, mg.

Active ingredient 50.0

Lactose 90.0

Milo starch 20.0

Corn starch 38.0

Calcium stearate 2.0 Total 200.0

Uniformly blend the active ingredient, lactose, starches and dicalciumphosphate when present. The blend is then granulated using water asgranulating medium. The wet granules are passed through an eightmeshscreen and dried at -160 F. The dried granules are passed through aten-mesh screen, blended with the proper amount of calcium stearate, andthe granules converted into tablets on a suitable tablet press.

3. lnjectable2% sterile solution per cc Active ingredient 20 mg.Preservative, e.g. chlorobutanol 0.5% weight/volume Water for injectionq.s.

wherein;

R is selected from the group consisting of hydrogen and hydroxy, and

R is selected from the group consisting of a-phenyla-hydroxybenzyl,a-lower-alkyl-a-hydroxybenzyl,a-lower-alkyl-a-hydroxy-p-trifluoromethylbenzyl, phenyl,trifluoromethylphenyl and 3,5-di-lower-alkylphenoxy.

5. A compound of claim 1 which isl-nitroso-3-(mtrifluoromethylphenyl)3-pyrrolidinol.

6. A compound of claim 1 which isl-nitroso-3-(mtrifluoromethylphenyl)pyrrolidine.

7. A compound of claim 1 which is l-nitroso-3-(3,5-dimethylphenoxy)pyrrolidine.

2. A compound of claim 1 which is 1-nitroso- Alpha , Alpha-diphenyl-3-pyrrolidinemethanol.
 3. A compound of claim 1 which is1-nitroso- Alpha -propyl-Alpha -phenyl-3-pyrrolidinemethanol.
 4. Acompound of claim 1 which is 1-nitroso- Alpha -methyl-Alpha-(p-trifluoromethylphenyl)3-pyrrolidinemethanol.
 5. A compound of claim1 which is 1-nitroso-3-(m-trifluoromethylphenyl)3-pyrrolidinol.
 6. Acompound of claim 1 which is1-nitroso-3-(m-trifluoromethylphenyl)pyrrolidine.
 7. A compound of claim1 which is 1-nitroso-3-(3,5-dimethylphenoxy)pyrrolidine.